Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism
Structure shows that a glycosaminoglycan and protein recognition site in factor H is perturbed by age-related macular degeneration-linked single nucleotide polymorphism
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DOI：
10.1074/jbc.m609636200
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发表时间：
2007-06-29
影响因子：
4.8
通讯作者：
Barlow, Paul N.
中科院分区：
文献类型：
--
作者：
Herbert, Andrew P.;Deakin, Jon A.;Barlow, Paul N.
一种常见的单核苷酸多态性因子H基因易患年龄相关性黄斑变性。因子H阻断补体在带有特定聚阴离子的自身表面上的旁路途径，包括蛋白聚糖的糖胺聚糖链。因子H也结合C-反应蛋白，可能有助于非炎性凋亡过程。风险序列在第402位（成熟蛋白中为384位）含有His（而不是Tyr），位于因子H的20个补体控制蛋白（CCP）模块（CCP 7）的第7位。我们表达了CCP 7、CCP 7、8和CCP 6 -8的His 402和Tyr（402）变体。我们确定了His（402）和Tyr（402）CCP 7的结构，并表明它们几乎相同。His/Tyr（402）的侧链具有类似的溶剂暴露取向，远离与CCP 6和-8的界面。Tyr（402）CCP 7与肝素亲和柱以及凝胶迁移率变动测定中使用的确定长度硫酸化肝素寡糖的结合比His（402）CCP 7显著更紧密。这一观察结果是一致的位置的402侧链的边缘上的两个糖胺聚糖结合的表面补丁的CCP 7，我们推断的基础上的化学位移微扰研究与硫酸化肝素四糖。根据表面等离子体共振测量，Tyr（402）CCP 6 -8比His（402）CCP 6 -8显著更紧密地结合固定的C反应蛋白。这些数据支持H402 Y和年龄相关性黄斑变性之间的因果关系，其中位置402的变化调节因子H对年龄相关性黄斑糖胺聚糖组成和凋亡活性变化的反应。
A common single nucleotide polymorphism in the factor H gene predisposes to age-related macular degeneration. Factor H blocks the alternative pathway of complement on self-surfaces bearing specific polyanions, including the glycosaminoglycan chains of proteoglycans. Factor H also binds C-reactive protein, potentially contributing to noninflammatory apoptotic processes. The at risk sequence contains His ( rather than Tyr) at position 402 (384 in the mature protein), in the seventh of the 20 complement control protein (CCP) modules (CCP7) of factor H. We expressed both His402 and Tyr(402) variants of CCP7, CCP7,8, and CCP6-8. We determined structures of His(402) and Tyr(402) CCP7 and showed them to be nearly identical. The side chains of His/Tyr(402) have similar, solvent-exposed orientations far from interfaces with CCP6 and -8. Tyr(402) CCP7 bound significantly more tightly than His(402) CCP7 to a heparin affinity column as well as to defined-length sulfated heparin oligosaccharides employed in gel mobility shift assays. This observation is consistent with the position of the 402 side chain on the edge of one of two glycosaminoglycan-binding surface patches on CCP7 that we inferred on the basis of chemical shift perturbation studies with a sulfated heparin tetrasaccharide. According to surface plasmon resonance measurements, Tyr(402) CCP6-8 binds significantly more tightly than His(402) CCP6-8 to immobilized C-reactive protein. The data support a causal link between H402Y and age-related macular degeneration in which variation at position 402 modulates the response of factor H to age-related changes in the glycosaminoglycan composition and apoptotic activity of the macula.